The Lipid Peroxidation By-product 4-Hydroxynonenal is Toxic to Axons and Oligodendrocytes

Abstract

Lipid peroxidation and the cytotoxic by-product 4-hydroxynonenal (4-HNE) have been implicated in neuronal perikaryal damage. This study sought to determine whether 4-HNE was involved in white matter damage in vivo and in vitro. Immunohistochemical studies detected an increase in cellular and axonal 4-HNE within the ischemic region in the rat after a 24-hour period of permanent middle cerebral artery occlusion. Exogenous 4-HNE (3.2 nmol) was stereotaxically injected into the subcortical white matter of rats that were killed 24 hours later. Damaged axons detected by accumulation of beta-amyloid precursor protein (beta-APP) were observed transversing medially and laterally away from the injection site after intracerebral injection of 4-HNE. In contrast, in the vehicle-treated animals, axonal damage was restricted to an area immediately surrounding the injection site. Exogenous 4-HNE produced oligodendrocyte cell death in culture in a time-dependent and a concentration-dependent manner. After 4 hours, the highest concentration of 4-HNE (50 micromol/L) produced 100% oligodendrocyte cell death. Data indicate that lipid peroxidation and production of 4-HNE occurs in white matter after cerebral ischemia and the lipid peroxidation by-product 4-HNE is toxic to axons and oligodendrocytes.

Ebselen Protects Both Gray and White Matter in a Rodent Model of Focal Cerebral Ischemia

“…Inhibition of 4-HNE by ebselen is particularly important because 4-HNE is not only a marker of lipid peroxidation but is also toxic to neurons, axons, and oligodendrocytes in its own right. 24,39 4-HNE generated during ischemia and reperfusion is therefore a likely contributory factor to the total amount of damage produced in this model. Both ebselen 40 and glutathione, the endogenous substrate for glutathione peroxidase, 41 have been reported to inhibit 4-HNE toxicity in cultured neurons.…”

“…Adjacent sections were processed for immunohistochemistry with Tau-1 antibody used to label ischemic oligodendrocytes 22 in both gray and white matter, anti-amyloid precursor protein (APP) to label ischemically damaged axons (disruption of axoplasmic flow leads to APP accumulation), and 8-OHdG 23 and 4-HNE 24 antibodies to identify DNA damage and lipid peroxidation, respectively, produced by oxidative stress. Sections were mounted on poly-L-lysine-coated (SIGMA) slides, dried at 37°C overnight, then placed in Histoclear for 20 minutes to remove the wax and dehydrated in absolute alcohol for 20 minutes.…”

Hyperglycemia Accelerates Apparent Diffusion Coefficient-Defined Lesion Growth after Focal Cerebral Ischemia in Rats with and Without Features of Metabolic Syndrome

“…34 Light microscopy was used to transcribe the location of increased 4-HNE immunostaining (compared with contralateral tissue) onto a separate set of eight coronal stereotaxic line diagrams, to those used for infarct measurements, and ImageJ was used to determine the volume of 4-HNE staining for each animal. This analysis was performed masked to the infarct volume data.…”

A radical approach to stroke therapy

“…Unlike NMDA receptor antagonists, brainpenetrating drugs with antioxidant affects protect not only neuronal perikarya but also axons and oligodendrocytes as well as improving neurological outcome after focal ischemia in rats (19). The view that oxidative damage is a crucial target for therapeutic intervention is further supported by evidence that oxidative stress and lipid peroxidation by-products are toxic to axons and oligodendrocytes as well as to neuronal perikarya (20,21). The nonselective nature of oxidative damage means that it has the potential to involve all cellular types and cellular components of normally functioning brain tissue: neuronal perikarya, axons, oligodendrocytes, astrocytes, microglia, and endothelial cells (Fig.…”